Mixed-ligand ruthenium polypyridyl complexes as apoptosis inducers in cancer cells, the cellular translocation and the important role of ROS-mediated signaling

Abstract

Ruthenium (Ru) polypyridyl complexes have emerged as leading players among the potential metal-based candidates for cancer treatment. However, the roles of cellular translocation in their action mechanisms remain elusive. Herein we present the synthesis and characterization of a series of ruthenium (Ru) complexes containing phenanthroline derivatives with varying lipophilicities, and examine their mechanism of anticancer action. Results showed that increasing the lipophilicity of complexes can enhance the rates of cellular uptake. The in vitro anticancer efficacy of these complexes depended on the levels of ROS overproduction, rather than on cellular Ru uptake levels. The introduction of a phenolic group on the ligand effectively enhanced their intracellular ROS generation and anticancer activities. In particular, complex 4, with an ortho-phenolic group on the ligand, exhibited better selectivity between cancer and normal cells in comparison with cisplatin. Notably, complex 4 entered the cancer cells partially through transferrin receptor-mediated endocytosis, and then it translocated from lysosomes to the mitochondria, where it activated mitochondrial dysfunction by regulation of Bcl-2 family proteins, thus leading to intracellular ROS overproduction. Excess ROS amplified apoptotic signals by activating many downstream pathways such as p53 and MAPK pathways to promote cell apoptosis. Overall, this study provides a drug design strategy for discovery of Ru-based apoptosis inducers, and elucidates the intracellular translocation of these complexes.

Investigation of inducing apoptosis in human lung cancer A549 cells and related mechanism of a ruthenium(II) polypyridyl complex

“…4A, phosphorylation of MAPKs was activated in Ru2-induced apoptotic pathways, and there was no significant change in phosphorylation of AKT. Notably, Ru2 treatment up-regulated the phosphorylation level of ERK (p-ERK) dramatically, which was not in accordance with previous reported of ruthenium complexes [8][9][10]. Moreover, the level of p-ERK increased in a time-dependent manner (Fig.…”

“…Although many studies on the abilities of Ru(II) polypyridyl complexes to modulate the ERK signaling pathways have been reported [8][9][10], data on the effect of these complexes on ERK activation and subsequent cellular responses remain limited. Hence, in this study, two compounds containing 2,2-bipyridine (bpy) ligands with 3-(pyrazin-2-yl)- [1,2,4] triazino [5,6-f] [1,10]phenanthroline (pztp) or 3-(pyridin-2-yl)- [1,2,4] triazino [5,6-f] [1,10]phenanthroline (pytp) as main ligands; Ru1 and Ru2 (Fig.…”

Cellular localization of iron(II) polypyridyl complexes determines their anticancer action mechanisms

“…Studies also reported that Ru(II) dipyridophenazine complexes can could mainly accumulate in the cytoplasm of live cells but were mostly excluded from the nucleus [35]. Our previous study also presented that the lipophilicity Ru(II) polypyridyl complexes located in mitochondria and induced apoptosis in cancer cells [36,37]. Besides Ru(II) complexes, other metal complexes, such as Pt(II), Au(III), Cu(I) and Ir(III) have been investigated for their relationship between cellular localization and anticancer action mechanisms [31,38e40].…”

A multifunctional DNA origami as carrier of metal complexes to achieve enhanced tumoral delivery and nullified systemic toxicity

“…Afterwards, the DNA cages were exploited to ferry transcription factor protein (catabolite activator protein, CAP) through non-covalent interaction [26]. Based on the desired biochemical properties of DNA cages, including superior biocompatibility, superior stability, enhanced cellular uptake/longer retention time, higher capacity-loading space and excellent affinity with metal complexes ( we have previously demonstrated [27,28]), we considered DNA cages as rational nanocarrier of Ru complexes to achieve improved drug delivery in cancer treatment. Despite the abovementioned potency, the strategy of positive targeting is still needed to endow the DNA nanosystem with maximum antitumoral efficiency and minimal side effects.…”